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Premature infants, particularly those born at <28 weeks’ gestation,
are at significant risk for reduced bone mineral content (BMC)
and subsequent bone disease, variably termed metabolic bone
disease (MBD), osteomalacia, osteopenia, or neonatal rickets.1,2
Reduction in BMC and the development of MBD of prematurity
are quite common among VLBW infants. However, due to the lack
of widely adopted diagnostic criteria, the true incidence
has not been determined. Fractures in premature infants typically
occur several weeks after delivery and prior to the postnatal
age of 6 months.3,4
Rib fractures, the most common type, usually occur silently
and are diagnosed only if x-rays are performed. Therefore,
the true incidence of fractures is difficult to determine,
varying between 2.1% and 25% in 3 previous studies3,4
conducted without the use of prospective, systematic skeletal
surveys.
The risk factors commonly associated with fractures include
extremely low birth weight, late (> 30 days) establishment
of full enteral feeds or prolonged parenteral nutrition, exclusive
use of unfortified human milk, necrotizing enterocolitis,
conjugated hyperbilirubinemia, chronic lung disease, use of
various medications, utilization of passive respiratory physiotherapy
(ie, chest percussion), and lack of physical activity, which
may be enhanced by sedatives. Recent data on fractures among
VLBW infants are still lacking, but some clinical evidence
suggests that the risk for fracture is greatly reduced with
the use of parenteral and enteral nutrition adapted to the
special nutritional needs of the premature infant.
Fetal accretion of calcium and phosphorus in the last trimester
of pregnancy is approximately 20 g and 10 g, respectively,
representing accretion rates of 100 to 120 mg/kg/day for calcium
and 50 to 65 mg/kg/day for phosphorus. This transfer is fairly
stable and relatively independent of the mother’s nutritional
status.1
By contrast, 25-hydroxyvitamin D [25(OH)D] from the mother
is the major source of vitamin D for the fetus as well as
for the newborn, until the infant receives vitamin D from
other dietary sources, such as formula or supplements. Fetal
vitamin D concentration is directly related to the mother’s
vitamin D status and thus to the season, the mother’s skin
pigmentation, sunlight exposure, and vitamin D supplementation.
Several recent studies have reported a high prevalence of
vitamin D insufficiency among pregnant women and their offspring,
suggesting that the resurgence of rickets in the United States
and several other nations worldwide is related to maternal
deficiencies.5,6
1,25-Dihydroxyvitamin D [1,25-(OH)2D], the physiologically
active metabolite of vitamin D, does not cross the placenta.
However, the ability of the placenta to synthesize 1,25-(OH)2D
directly is important in the transfer of phosphate to the
fetus and contributes to the infant’s circulating level of
25(OH)D.7
Thus, as a result of placental insufficiency, some pre-term
infants born with severe growth restriction are phosphate-deficient,
which increases their risk for MBD. In addition to the effect
of vitamin D on numerous other non-skeletal health outcomes,
emerging data demonstrate that vitamin D regulates placental
development and function, suggesting that maternal vitamin
D status may be associated with such adverse pregnancy outcomes
as miscarriage, preeclampsia, and pre-term birth.5,6
Risk factors for MBD are commonly encountered in the pre-term
infant. The majority of bone mineralization, along with calcium
and phosphorus accretion, occurs during the third trimester
of pregnancy. Infants born before this time thus have depleted
stores of these minerals.4
Data from bone density scans (dual-energy x-ray absorptiometry
[DEXA]) performed at birth in pre-term and term infants suggest
that bone mineral accretion during the last trimester of gestation
is higher than needed, with growth in bone volume leading
to a continuous increase in skeletal density.1
Pre-term infants therefore have a large mineral deficit compared
with term infants. Several factors increase the risk for severe
MBD among VLBW infants, with the most important appearing
to be an inadequate supply of calcium and phosphorus associated
with the use of an enteral vs transplacental route. Newborn
premature infants experience a diminished mineral uptake required
for proper bone accretion, due, in part, to the reduced availability
and to their compromised gastrointestinal (GI) absorption.
Relative calcium absorption, which depends on calcium bioavailability
and vitamin D intake, appears to be significantly higher in
pre-term infants fed fortified human milk (± 50% to 60%) than
in those fed formula (35% to 50%).8
By contrast, phosphorus intake is generally well absorbed
(± 90%) in either group.8
The retention of calcium and inorganic phosphate is interrelated,
based on the calcium to phosphate ratio of hydroxyapatite
and the inorganic phosphate to nitrogen retention ratio. Thus,
metabolic balance studies8
have reported that maximal calcium retention values may reach
60 to 90 mg/kg/day and maximal inorganic phosphate retention
values may reach 50 to 75 mg/kg/day. The retention rates are
relatively low compared with the fetal accretion rates. In
total parenteral nutrition, similar data could be obtained
with the use of organic phosphate supply and highly soluble
calcium salt. In our unit, we use calcium glycerophosphate,
which allows us to provide up to 105 mg of calcium and 80
mg of inorganic phosphate/kg/day.
Decreased bone mineralization and the development of osteopenia
are the balanced result between 2 different bone matrix growth
factors, directly related to energy balance and nitrogen retention
on the one hand, and mineral accretion on the other hand.1
Data from DEXA scans1,8
performed during the first weeks after birth in both pre-term
and term infants suggest that bone growth, estimated by increase
in bone area, is relatively higher than bone mineral accretion,
leading to a continuous decrease in skeletal density. Nevertheless,
after a few weeks or months, with the continuous reduction
in growth velocity, the balance is progressively reversed
and the bone mass accrual compensates slowly for the early
peak bone growth during the first few months of life.
Physical activity appears to play a significant role in bone
mineralization. During the neonatal period, mechanical strain
on bone and joints stimulates bone formation and growth, whereas
inactivity leads to bone resorption. This might be equally
valid for pre-term infants in incubators during the first
weeks of life, who lack the in utero mechanical stimulation
associated with regular kicks against the confining uterine
wall. During the initial hospitalization, the movements of
pre-term infants usually occur without much resistance. While
in the NICU, these infants are handled with little tactile
stimulation in order to reduce stressful events. Moreover,
the use of drugs to reduce pain aggravates the reduction in
mechanical stimulation during their stay. In order to obviate
the effects of reduced mechanical stimulation, systematic
physical activity programs administered several times a week
by nurses, therapists, and parents have been evaluated. A
number of recent studies, including one by Moyer-Mileur and
colleagues (reviewed herein), agree that physical activity
either improves bone mineralization, as determined by single-photon
absorptiometry, or increases bone formation, as estimated
by the measure of serum collagen C-terminal propeptide. These
regimens either increased bone strength or attenuated its
decrease, as evaluated by quantitative measurement of bone
ultrasound transmission speed. Nevertheless, the last Cochrane
review of this subject (Schulzke et al. discussed in this
issue), concluded that additional studies are needed before
the general use of such physical activity programs can be
promoted.
A number of other factors may also play a significant role
in bone mineralization, including genetic polymorphism, mechanical
stimulation, or the use of various medications that interfere
with mineral absorption or retention, such as diuretics, caffeine,
and corticosteroids.
Neonatal screening for MBD in pre-term infants is still controversial.2,4
Serum calcium levels are carefully regulated by hormonal secretion
and are not a useful screening tool. However, a low serum
phosphorus concentration <1.8 mmol/L) that is below
the renal phosphate threshold has been related to insufficient
phosphorus intake and to an increased risk for osteopenia.
Urinary excretion of calcium and phosphorus has been proposed
as a marker of adequate postnatal mineralization when doses
>1.2 mmol/L of calcium and >0.4 mmol/L of inorganic phosphorus
are excreted simultaneously. However, these values are more
appropriate for estimating the adequacy of the calcium to
phosphate ratio than for estimating mineral accretion, especially
when data on the mineral absorption rate are lacking.
In infants, 90% of alkaline phosphatase (ALP) is of bone origin
and thought to reflect bone turnover. ALP concentrations usually
increase during the first 2 to 3 weeks of life and may peak
further if there are insufficient mineral supplies. Elevated
levels of ALP have been reported in association with severe
undermineralization based on radiologic evidence, low bone
speed of sound (SOS) using quantitative ultrasound, or severe
bone mineral density (BMD) deficit revealed on DEXA scans.
Nevertheless, ALP is probably more sensitive for evaluating
fracture risk than for assessing MBD or osteopenia.
Various radiologic investigations have been proposed for assessing
bone mineralization and osteopenia among pre-term infants.
Plain radiography is poorly sensitive, detecting only a decrease
of >20% to 40% of bone mineralization.4
By contrast, DEXA technology, reviewed by Pieltain and colleagues
in this issue, is sensitive, accurate, and precise, and its
use has been validated in both pre-term and term infants.1,8
Normative data on bone mineral content, projected bone area,
and BMD in healthy pre-term and term infants close to birth
were established in order to obtain surrogate intrauterine
reference values. In addition, various indices have been proposed
for reducing the anthropometric dependency of the various
parameters and for facilitating group or individual comparison.
Thus, data obtained from various groups allow for the determination
of major changes in bone mineralization during the fetal life
and postnatally in pre-term and term infants. These results
are in agreement with the predicted time course of volumetric
bone mineral density in mature newborns and premature babies,
according to mechanostat theory.2
The use of ultrasound has been proposed for the evaluation
of bone mineralization in newborn infants.8
It is a simple, non-invasive, relatively inexpensive bedside
procedure. Some machines have been designed to measure broadband
ultrasound attenuation or SOS, commonly on the tibia. The
propagation of sound waves in bone is determined by a number
of factors, including mineral density, cortical thickness,
elasticity, and micro-architecture, possibly providing a more
complete picture of bone strength than measurements of BMD
alone. In pre-term and term infants at birth, there is a significant
correlation among tibial SOS and gestational age, birth weight,
birth length, and tibial length. However, the changes in SOS
values during the last trimester of gestation are relatively
small, accounting for only about 130 m/sec. This value is
only ±1.5 times higher than the interindividual variability
(standard deviation [SD]=95 m/sec). After birth, a rapid decline
in bone SOS occurs during the first days of life that cannot
be completely explained by a nutritional deficit. Therefore,
these data suggest that measurement of bone SOS has a lower
sensitivity than DEXA for evaluating the various factors influencing
bone mineralization during the neonatal period.
In contrast to fetal bone metabolism, in which modeling is
the main process inducing high net bone formation, with a
rapid increase in trabecular thickness, neonatal bone metabolism
is the result of a prevailing remodeling activity, defined
as the cyclical succession of bone resorption and formation
on the same bone surface.1,2
Therefore, the relative MBD of prematurity could be the result
of a postnatal physiologic metabolic adaptation instead of
the expression of a transitory MBD. Indeed, the relative osteopenia
observed in pre-term infants appears to be similar to that
observed in healthy term infants during the first weeks after
delivery or to that observed in early adolescence at the time
of a growth spurt.
Currently, calcium and phosphorus requirements in pre-term
infants are usually based on demands for matching intrauterine
bone mineral accretion rates. Recent recommendations from
North America1
suggest that mineral requirement in VLBW infants are as high
as 120 to 220 mg/kg per day for calcium and 60 to 140 mg/kg
per day for phosphorus. However, a recently acquired understanding
of bone physiology suggests that the mere adaptation of the
neonate to its extrauterine environment could modify the calcium
requirements, as the stimulation of the remodeling process
might contribute to the mineral requirements for postnatal
bone turnover. In addition, in spite of their low absorption
rate, the high-calcium formulas used in pre-term infants might
pose a risk for VLBW infants. Therefore, new recommendations
have been proposed by the European Society for Pediatric Gastroenterology,
Hepatology and Nutrition Committee on Nutrition, based on
the fact that a calcium retention level ranging from 60 to
90 mg/kg/day ensures appropriate mineralization, decreases
the risk for fracture, and reduces the clinical symptoms of
osteopenia. Thus, an intake of 100 to 160 mg/kg/day of highly
bioavailable calcium salts, 60 to 90 mg/kg/day of phosphorus,
and 800 to 1000 IU/day of vitamin D have been recommended.1
In summary, after birth, the development of relative osteomalacia
or osteopenia is a physiologic event resulting from a mismatch
of the mineral supply and the persistent growth velocity on
the one hand, and from the stimulation of bone turnover as
an adaptation to extrauterine life on the other. This phenomenon
is enhanced in pre-term infants born with low mineral stores,
an immature GI tract, and reduced physical activity, who demonstrate
higher growth rates than do term infants. Several of the conditions
discussed above and in the articles reviewed in this issue
might increase the severity of MBD, leading to the development
of severe osteopenia and the risk for fracture. Early optimal
parenteral and oral nutritional support, combined with biologic
neonatal screening and measurement of serum phosphorus and
ALP concentrations, as well as mineral urinary excretion,
appears to be helpful for the prevention of MBD. When available,
DEXA is more sensitive than ultrasound for quantifying osteopenia
in VLBW infants.
References
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J, Pieltain C, Salle B, Senterre J. Enteral
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C, Schoenau E. Fetal
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Bishop
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Arch Dis Child. 2007;92(3):251-256. |
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CM, Johnson K, McKechnie E. Osteopenia
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Bodnar
LM, Simhan HN, Powers RW, Frank MP, Cooperstein E, Roberts
JM. High
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Arch Dis Child. 2007;92(9):737-740. |
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